The overall goal of the proposed research is to determine the development and function of endogenous opioid systems in regulation of cardiovascular activity in the mammalian fetus. Both in vivo and in vitro studies will be conducted into the regulation of fetal cardiovascular activity by endogenous opioid systems. Regulation of fetal heart rate, blood pressure, and cardiac output by endogenous opioid systems will be assessed by opioid antagonist blockade in control and hemorrhaged fetuses. Fetal cardiovascular responses will be characterized to opioid agonists selective for each of the three major opioid receptor subtypes. These studies will be correlated with in vitro studies on the development of three well-defined opioid receptor subtypes in the pons-medulla of brainstem, a major center for central regulation of blood pressure. In addition, interactions between opioid and adrenergic systems will be investigated in both control and hemorrhaged fetuses. Fetal cardiovascular responses to opioid antagonist administration will be assessed in the presence of alpha and beta-adrenergic receptor blockade. The chronically cannulated lamb fetus is the animal model chosen for study. With this model it is possible to study opioid effect in the fetus in the absence of complicating factors of anesthesia and surgical trauma, both of which are inherent in acute animal preparations. In addition, the sheep fetus provide sufficient tissue for in vitro studies of opioid receptor systems within specific brain regions. The information derived from these proposed studies will further our understanding of physiological regulation of fetal cardiovascular activity by intrinsic opioid systems. These studies will also provide information on the maturation of pharmacological responses in the fetus to exogenously administered opioid compounds. Overall, these studies will contribute significantly to our present knowledge of hemeostatic mechanisms responsible for fetal maintenance during gestation.